Anilide and cyclodextrin complexes, their preparation and their use as medicine in particular for treating dyslipidemiae

ABSTRACT

The invention concerns more particularly dodecylthio-phenylacetanilide derivative complexes such as (S)-2′,3′,5′-trimethyl-4′-hydroxy-α-dodecylthio-phenylacetanilide or related derivatives thereof and cyclodextrins.

[0001] This invention relates to complexes between polycarbon-chainanilide derivatives and cyclodextrins, and also to the pharmaceuticalcompositions containing them.

[0002] The polycarbon-chain anilide derivatives are more particularlydodecylthiophenylacetanilide derivatives, such as(S)-2′,3′,5′-trimethyl-4′-hydroxy-α-dodecylthiophenylacetanilide(laboratory code: F12511) or related derivatives thereof.

[0003] They are derivatives which are either crystalline, correspondingto a defined crystalline form or to a mixture of defined crystallineforms, or amorphous, i.e. with no particular crystalline form.

[0004] They are inhibitors of acyl cholesterol acyl transferase (orACAT), an enzyme which catalyzes the esterification of free cholesterol,thus allowing intracellular storage of cholesterol, in the form ofcholesterol linked to fatty acids.

[0005] They are molecules of choice for the treatment, of dyslipidemias,such as hypercholesterolemia, and the prevention of atherosclerosis.

[0006] F12511 is a non-salified molecule, of empirical formulaC₂₉H₄₃NO₂S and of molecular mass 479.73 g.

[0007] Its structural formula is:

[0008] This molecule is virtually insoluble in water and the solventswhich are usually used in pharmaceutical formation and physiologicallycompatible with essentially oral or parenteral administration.

[0009] By way of example, the table below gives some characteristicsolubilities at saturation, at 25° C.: Solubility at saturation Solventexpressed in mg/ml Water less than 50 × 10⁻⁶⁽¹⁾ Ethanol 7 Macrogol 400 1Corn oil   0.3

[0010] It is known, that hydrophilic solvents such as ethanol orMacrogol 400 cannot be used pure; unfortunately, adding water veryrapidly causes the solubility of F12511 to decrease, as reflected by theresult obtained with ethyl alcohol at 95%, where the solubility atsaturation is no more than 2 mg/ml.

[0011] Finally, the use of surfactants in aqueous solution does notenable better results to be obtained. For example, the amount of F12511solubilized after 2 hours of stirring in an aqueous solution containing5% of sodium lauryl sulfate is approximately 10 μg/ml, at 25° C.

[0012] The cyclodextrins were discovered approximately one hundred yearsor so ago (Pr D. Duchene, F. Glomot and Dr C. Vaution Cyclodextrins andtheir industrial uses (Editions de Santé, 1987) Chapter 6:Pharmaceutical applications of cyclodextrins, p. 213). Initially, onlysmall amounts of relatively impure cyclodextrins were isolated, buttheir high production cost prevented them being used industrially.

[0013] Recent progress in biotechnology has had the effect ofconsiderably improving the production yield thereof, decreasing the costof these materials and making possible the use of highly purifiedcyclodextrins or cyclodextrin derivatives.

[0014] Cyclodextrins come from the enzymatic degradation of starch, thetwo main constituents of which are: branched amylopectin andlinear-chain amylose.

[0015] The partial degradation products of these two macromolecules arecalled dextrins.

[0016] Specific enzymes exist which not only degrade the macromoleculesto smaller units (dextrins) but simultaneously also produce cyclicdextrins: cyclodextrins. These are cyclic oligosaccharide compoundswhich, depending on the reaction conditions, comprise mainly 6, 7 or 8glucose units linked via α-(1,4) linkages: reference is then made to α-,β- and γ-cyclodextrin.

[0017] Native cyclodextrin molecules form toroidal structures, theoutside of which is hydrophilic and the inside of which is hydrophobic.Their water-solubilities are, respectively, at 25° C.: α-cyclodextrin:14.2 g % ml, β-cyclodextrin:  1.8 g % ml, γ-cyclodextrin: 23.2 g % ml.

[0018] Cyclodextrin derivatives have been prepared in order to increasethis water-solubility. Hydroxypropyl-β-cyclodextrin and sulfobutyl etherβ-cyclodextrin have a solubility of greater than 50 g % ml. Somemethylated derivatives have a solubility also greater than 50 g % ml,such as heptakis(2,6-di-O-methyl)-β-cyclodextrin, or DIMEB, or evengreater than 200 g % ml, such as the randomly methylated β-cyclodextrinderivative or RAMEB.

[0019] The exact value of the solubility depends on the degree ofsubstitution of the cyclodextrin derivative considered.

[0020] This list is not limiting: the previous examples are given onlyto illustrate the possibilities of increasing the water-solubility ofnative cyclodextrins by preparing suitable derivatives which are clearlymore soluble.

[0021] The present invention relates to complexes of polycarbon-chainanilide derivatives and of cyclodextrins, more particularly ofdodecylthiophenylacetanilide derivatives, such as(S)-2′,3′,5′-trimethyl-4′-hydroxy-α-dodecylthiophenylacetanilide(F12511) or related derivatives thereof, and of cyclodextrins, moreprecisely of α-, β- and γ-cyclodextrins and derivatives thereof, such ashydroxypropyl, sulfobutyl ether or methylated derivatives.

[0022] These complexes are inclusion complexes or complexes formed bymultiple interactions and, more generally, by surface interactions whichcan be observed in solid dispersions.

[0023] The complexes which are the subject of the invention made up ofACAT-inhibiting polycarbon-chain anilide derivatives and ofcyclodextrins have a solubility in aqueous medium which is considerablygreater than that of the polycarbon-chain anilide derivative alone.

[0024] Moreover, the capacity for micellization of the ACAT-inhibitingpolycarbon-chain anilide derivatives, by surfactants such as sodiumlauryl sulfate, is unexpectedly multiplied by a not insignificant factorin the presence of these complexes.

[0025] The polycarbon-chain anilide derivatives are amorphous orcrystalline. In the latter case, this may be a single crystalline formor a mixture of various crystalline forms.

[0026] Four types of methods for preparing the activeprinciple:cyclodextrin complexes can be used. They differ from oneanother through the nature of the reaction medium: semi-solid, solid orliquid.

[0027] Type 1: In the case of semi-solid preparations, the activeprinciple/cyclodextrin complexation is performed by kneading in thepasty state, in the presence of a small amount of liquid, most commonlyof water, but also of ethanol, or of mixtures of water/ethanol, or anyother suitable hydrophilic cosolvent.

[0028] The method may be a batch method (for example kneading in asuitable mixer), or continuous method (for example extrusion).

EXAMPLE 1

[0029] The kneading is carried out in a BRABENDER mixer. The tank ofsaid mixer is equipped with a “Z”-shaped blade operated at 30 rpm. Amixture of 24.2 mmol of γ-cyclodextrin and 9.3 ml of purified water isintroduced into the mixer tank and kneaded until a homogeneous paste isobtained. 5.7 g of F12511 (12.1 mmol) are gradually added and kneaded atbetween 30° C. and 55° C. until the endothermic peak characteristic ofthe solid/liquid transition of F12511 has completely disappeared. Theproduct obtained is calibrated on a FREWITT oscillator and dried undervacuum at 40° C. for 12 hours.

[0030] It is characterized by:

[0031] Differential Thermal Analysis:

[0032] The differential thermal analysis is carried out by heating from30° C. to 280° C. at 10° C.min⁻¹ under nitrogen using a Perkin Elmer DSC7 device. The thermograms are given in FIG. 1. The thermogram for F12511(a) shows three main characteristic endothermic events. The endothermicpeak, centered over 102° C., of γ-cyclodextrin (b) corresponds to theevaporation of water. The thermogram for the simple physical mixtureF12511:γ-cyclodextrin, under dry conditions, at the molar ratio (1:2)(c) is the simple superposition of the thermograms for the purecompounds. The F12511:γ-cyclodextrin system at the molar ratio (1:2)after kneading (d) shows a single endothermic peak centered over 112°C., the endothermic events characteristic of F12511 having completelydisappeared.

[0033] Fourier Transform Infrared (FTIR) Spectroscopy:

[0034] The infrared spectra are produced according to the KBr-dispersionmethod using a Nicolet 310 FTIR spectrometer. FIG. 2 gives the IRspectra of the various systems, F12511 (a), γ-cyclodextrin (b). Thespectrum of the simple physical mixture F12511:γ-cyclodextrin, under dryconditions, at the molar ratio (1:2) (c) is the simple superposition ofthe spectra of the pure compounds. The spectrum of theF12511:γ-cyclodextrin mixture at the molar ratio (1:2) after kneading(d) shows a clear change compared to that of the simple physicalmixture, with, in particular, the disappearance of the band locatedbetween 1530 cm⁻¹ and 1540 cm⁻¹ characteristic of the deformation of theN—H bond of the amide group and of the valence vibration of the C═Cbonds of the aromatic rings of the F12511.

[0035] After stirring for 2 hours in an aqueous solution of sodiumlauryl sulfate at 5%, the amount of F12511 solubilized from theF12511:γ-cyclodextrin (1:2) complex is 560 μg/ml instead of 11 μg/ml forthe F12511 alone.

[0036] The active principle:cyclodextrin molar ratio used is animportant factor which conditions the degree of interaction between thetwo entities, as demonstrated in the following Examples 2 and 3:

EXAMPLE 2

[0037] The mixing is carried out under the same conditions as Example 1.Only the amounts of F12511 and of γ-cyclodextrin, calculated to obtain a1:1 molar ratio, vary. The differential thermal analysis carried out onthe product obtained indicates a percentage interaction in the region of60%. The amount of F12511 solubilized in an aqueous solution of sodiumlauryl sulfate at 5% is then only 385 μg/ml after stirring for 2 hours.

EXAMPLE 3

[0038] The kneading is carried out under the same conditions asExample 1. Only the amounts of F12511 and of γ-cyclodextrin, calculatedto obtain a 1:1.5 molar ratio, vary. The differential thermal analysiscarried out on the product obtained indicates a percentage interactionin the region of 80%. The amount of F12511 solubilized in an aqueoussolution of sodium lauryl sulfate at 5% is then only 495 μg/ml afterstirring for 2 hours.

[0039] Comment: In Examples 1 to 3, the method for preparing thecomplexes is carried out by forming a paste of γ-cyclodextrin withpurified water beforehand, and then adding the F12511. Other methods ofpreparation can be envisioned. In particular, an alternative method mayconsist in premixing F12511 and γ-cyclodextrin and then adding purifiedwater.

EXAMPLE 4

[0040] The kneading is carried out in a mortar.

[0041] Various F12511:methyl-β-cyclodextrin ratios are used, in thiscase 1:1, 1:2 and 1:3, in the presence of water. The mass of F12511treated is of the order of 500 mg. After drying in an incubator at 120°C., for 30 minutes, the final products are characterized by differentialthermal analysis on a Mettler Toledo Star $ System device.

[0042]FIG. 3 indicates that, despite the drying performed, residualwater remains present in the 3 compositions. The F12511 polymorphismpeak is observed at 110° C., but the melting peak is absent. Only anendothermic and then exothermic unresolved peak ending at 150° C. isrevealed. It is difficult to exploit the thermogram.

[0043] After cooling, a second differential thermal analysis is carriedout (FIG. 4). No enthalpic effect is observed. Only a glass transitionoccurs, the temperature of which increases when the amount ofmethyl-β-cyclodextrin increases.

[0044] It is clearly apparent that the methyl-β-cyclodextrin interactsin a very exceptional manner with the F12511.

EXAMPLE 5

[0045] Example 1 concerns the preparation, in the presence of water, ofan F12511:γ-cyclodextrin complex, at the 1:2 molar ratio, from a totalmass of mixture of approximately 40 g.

[0046] It is essential to verify that this complex can be producedcorrectly, firstly, by changing scale, i.e. by increasing the batchsize, and, secondly, by performing this change in scale on productiondevices for which models exist, both at the laboratory level and at thepilot and industrial levels, within the same homothetic range.

[0047] Z-blade mixers were used to do this.

[0048] By way of example two batches of almost 2 kg, i.e. 50 times 40 g,of complex were prepared by kneading on a WINKWORTH model 10Z mixer. Thetable below gives the production parameters used and the change in theamount of F12511 converted by interaction with γ-cyclodextrin over time,for a 1:2 molar ratio. Change in the Percentage percentage of water inRotation of F12511 Batch size the mixture Temperature speed converted(g) (%) (° C.) (rpm) over time 1979 25 35 20 10 min: 19% 20 min: 65% 30min: 91% 40 min: 95% 50 min: 97% 80 min: 97% 1979 25 35 40 10 min: 33%20 min: 93% 30 min: 96% 40 min: 96% 50 min: 98% 80 min: 98%

[0049] The kinetics for solubilization of these two batches in anaqueous solution of sodium lauryl sulfate at 5% are given in the tablebelow and FIG. 5. Amount of F12511 solubilized in a solution of sodiumlauryl sulfate at 5% (in μg/ml) Entity After After After After tested 5min 30 min 1 h 2 h F12511:γ- 258 579 663 698 cyclodextrin (1:2) Speed:20 rpm F12511:γ- 307 608 686 731 cyclodextrin (1:2) Speed: 40 rpm

[0050] Type 2: In solid medium, the active principle and thecyclodextrin are mixed in the pulverulent state and co-ground.

EXAMPLE 6

[0051] Co-grinding is carried out in a DANGOUMAU impact milling mill: 1g of equimolar mixture consisting of 0.57 mmol of F12511 and 0.57 mmolof β-cyclodextrin is introduced into a 65 cm³ steel pot containing analuminum bead 20 mm in diameter and 10 g in mass. The pot is subjectedto a vertical to-and-fro movement, at a frequency of 730 cycles perminute. The mixture is co-ground until the endothermic peakcharacteristic of the solid/liquid transition of the F12511 hascompletely disappeared.

[0052] The product obtained is characterized by:

[0053] Differential Thermal Analysis:

[0054] The differential thermal analysis is carried out by heating from30° C. to 280° C. at 10° C.min⁻¹ under nitrogen using a Perkin Elmer DSC7 device. The thermograms are given in FIG. 6. The thermogram for F12511(a) shows three main characteristic endothermic events. The endothermicpeak centered over 105° C. of β-cyclodextrin (b) corresponds to theevaporation of water. The thermogram for the simple physical mixtureF12511:β-cyclodextrin (c), under dry conditions, in equimolarproportions, is the simple superposition of the thermograms of the purecompounds. The co-ground equimolar mixture (d) shows a singleendothermic peak centered over 70° C., the endothermic eventscharacteristic of F12511 having completely disappeared.

[0055] Fourier Transform Infrared (FTIR) Spectroscopy:

[0056] The infrared spectra are produced according to the KBr-dispersionmethod using a Nicolet 310 FTIR spectrometer. FIG. 7 gives the IRspectra of the various systems: F12511 (a), β-cyclodextrin (b). Thespectrum for the equimolar physical mixture F12511:β-cyclodextrin (c) isthe simple superposition of the spectra for the pure compounds. Thespectrum for the co-ground equimolar mixture F12511:β-cyclodextrin (d)shows a clear change compared to that for the simple physical mixture:the disappearance of the band located between 1530 cm⁻¹ and 1540 cm⁻¹,characteristic of the deformation of the N—H bond of the amide group andof the valence vibration of the C═C bonds of the aromatic rings of theF12511, is in particular noted.

EXAMPLE 7

[0057] The co-grinding is carried out under the same conditions asExample 6.

[0058] The F12511:β-cyclodextrin mixture used corresponds to the molarratio (1:2). It consists of 0.32 mmol of F12511 and 0.64 mmol ofβ-cyclodextrin.

[0059] This mixture is co-ground until the endothermic peakcharacteristic of the solid/liquid transition of F12511 has completelydisappeared.

[0060] The differential thermal analysis and the Fourier TransformInfrared spectroscopy carried out on the final product show the absenceof the free F12511.

[0061] The F12511:β-cyclodextrin complexes derived from the preparationsdescribed in the preceding Examples 6 and 7 were solubilized in anaqueous solution of sodium lauryl sulfate at 5%: after standing for 2hours, the amounts of F12511 solubilized are, respectively, 420 and 210μg/ml for the F12511:β-cyclodextrin molar ratios 1:1 and 1:2.

[0062] Examples 6 and 7 illustrate the preparation, by co-grinding, on alaboratory scale of F12511:β-cyclodextrin complexes with respectivemolar ratios of 1:1 and 1:2 for a total mass of 1 g.

[0063] The possibility of changing scale, and therefore ofindustrializing of the co-grinding process, was verified by using 1500 gof an F12511:β-cyclodextrin (1:2), mixture in a DM1 vibrating mill fromthe company SWECO, filled with 45 kg of milling medium.

[0064]FIG. 8 shows the change in the percentage of complexation ofF12511 during the co-grinding: conversion is complete for the sampletaken after 36 h of treatment.

[0065] The above results clearly illustrate the possibility ofcomplexing ACAT-inhibiting polycarbon-chain anilide derivatives andcyclodextrins using high energy co-grinding.

[0066] Other mills can also be used, in particular the Hybridizer systemfrom the company NARA which uses powder surface modification technology(high energy impact or particle design mill) and which offers theadvantage of a very short duration for the process.

EXAMPLE 8

[0067] Co-grinding is carried out in a Hybridizer system, model NHS-0.20g of mixture consisting of 6.33 mmol of F12511-and 12.66 mmol ofβ-cyclodextrin are introduced and co-ground at a rotation speed of 16200rpm. After only 5 minutes of process, the product obtained alreadyshows, by differential thermal analysis, a percentage of interaction of75%.

[0068] After stirring for 2 hours in an aqueous solution of sodiumlauryl sulfate at 5%, the amount of F12511 solubilized from thisco-ground material is 105 μg/ml.

[0069] Type 3: In semi-solid or solid medium:

[0070] Independently of the physical nature of the reaction medium, thecomplexation of polycarbon-chain anilide derivatives with cyclodextrinsoccurs from the moment energy is introduced into the simple physicalmixing of the two components, in the presence or absence of water,whether this energy is mechanical and/or thermal and/or developed byhigh pressures, as confirmed in the example below, which illustrates thecombined action of a gentle mechanical energy with high temperatures andhigh pressures.

EXAMPLE 9

[0071] 40 g of a mixture of F12511:γ-cyclodextrin, in a 1:2 molar ratio,containing 25% of water, are introduced into a stainless steel cylinderequipped with a sintered glass funnel at each end.

[0072] The F12511, as in the preceding examples, is generatedchemically. This cylinder is placed in a high pressure autoclavepreheated at 100° C.

[0073] Carbonic anhydride is introduced into the autoclave andpressurized at 300 bar.

[0074] After stabilization of the temperature and the pressure, twosamples of mixture are taken after, respectively, 1 hour and 16 hours ofcomplexation. They are ground and calibrated.

[0075] For the 1-hour sample, the differential thermal analysis revealsa degree of F12511:γ-cyclodextrin complexation of greater than 75%.

[0076] For the 16-hour sample, this degree of complexation is in theregion of 95%. The solubilization kinetics thereof indicate aconcentration of 520 μg/ml of solubilized F12511 after 2 hours ofstirring in an aqueous sodium lauryl sulfate solution at 5%.

[0077] Type 4: The principle of the method of preparation in liquidmedium is to bring the active principle and the cyclodextrin intocontact, in the molecular state, and then to isolate the complex formed,for example using suitable solvents or non-solvents.

EXAMPLE 10

[0078] A mixture of 200 ml of water containing 1.47 mmol ofβ-cyclodextrin and of 400 ml of tetrahydrofuran containing 2.94 mmol ofF12511 is stirred, by magnetic stirring, at 370 rpm, for a day, at atemperature of 40° C. After conservation at +5° C. for 3 days, aprecipitate has formed, which precipitate is collected by filtration anddried. The amount of product recovered is 549.4 mg; it contains theF12511 complexed with the β-cyclodextrin.

[0079] Depending on their characteristics, the complexes are alsorecovered by co-crystallization, evaporation, lyophilization ornebulization.

[0080] The complexes of polycarbon-chain anilide derivatives and ofcyclodextrins, more particularly of dodecylthiophenylacetanilidederivatives, such as(S)-2′,3′,5′-trimethyl-4′-hydroxy-α-dodecylthiophenylacetanilide orrelated derivatives thereof, and of native cyclodextrins or derivativesthereof, such as, respectively, α-, β-, γ-cyclodextrins orhydroxypropyl, sulfobutyl ether or methylated derivatives thereof,exhibit, surprisingly, solubilities in aqueous medium which areconsiderably greater than the solubilities of the initialpolycarbon-chain anilide derivatives.

[0081] It is recalled that the solubility at saturation in water ofF12511 is less than 50 ng/ml, this value in fact representing the limitof analytical detection of the molecule in saturated solution.

[0082] The kinetics for solubilization in water of theF12511:γ-cyclodextrin complex, at the molar ratio 1:2, show an amount ofsolubilized F12511 of between 1 and 2 μg/ml during the first two hoursof stirring.

[0083] The use of γ-cyclodextrin therefore makes it possible to multiplythe amount of F12511 solubilized in the water by a factor of at least 20to 40 times.

[0084] Moreover, the behavior of this same F12511:γ-cyclodextrin (1:2)complex in an aqueous solution of sodium lauryl sulfate at 5% reveals amicellization capacity for the surfactant which is multiplied up to 260times compared to the result obtained for F12511 alone, as indicated inthe table below and FIG. 9. Amount of F12511 solubilized in a solutionof sodium lauryl sulfate at 5% (in μg/ml) Entity After After After Aftertested 5 min 30 min 1 h 2 h F12511 1 3 5 11 F12511: 260 470 590 560γ-cyclodextrin (1:2)

[0085] The results are just as surprising with the F12511:β-cyclodextrincomplexes (1:1 and 1:2 molar ratios).

[0086] They are given in the table below and illustrated in FIG. 10.Amount of F12511 solubilized in a solution of sodium lauryl sulfate at5% (in μg/ml) Entity After After After After tested 5 min 30 min 1 h 2 hF12511 1 3 5 11 F12511: 400 455 505 420 β-cyclodextrin (1:1) F12511: 365360 350 210 β-cyclodextrin (1:2)

[0087] The capacity for micellization of the F12511 by sodium laurylsulfate can be multiplied up to 400 times compared to the resultobtained for F12511 alone.

[0088] In the active principle:cyclodextrin complexes obtained, themolar ratios of the two entities are variable: they are advantageouslybetween 1:5 and 5:1, more precisely between 1:1 and 1:3, and moreparticularly equal to 1:2.

[0089] The choice of the latter value is perfectly illustrated in thetable below, which gives, for example, for F12511:γ-cyclodextrin ratiosincreasing from 1:1 to 1:2 by increments of 0.1 for the γ-cyclodextrin:

[0090] firstly, the percentage complexation of the F12511 determined bydifferential thermal analysis,

[0091] secondly, the amount of F12511 solubilized in a solution ofsodium lauryl sulfate at 5% after stirring for 2 h.

[0092] The method for preparing the complex is kneading in aqueousmedium. Amount of F12511 F12511:γ- solubilized in a solutioncyclodextrin % complexation of sodium lauryl sulfate molar ratio ofF12511 at 5% after 2 h (in μg/ml) 1:1   61% 385 1:1.1 66% 400 1:1.2 70%409 1:1.3 75% 400 1:1.4 78% 457 1:1.5 83% 495 1:1.6 85% 509 1:1.7 90%560 1:1.8 92% 570 1:1.9 94% 583 1:2   100%  560

[0093] The increase in the rate of dissolution noted in aqueous medium,for polycarbon-chain anilide active principles belonging to SUPACclasses II and IV of the American Food and Drug Administration due totheir low 20 solubility, and more specifically to class IV with regardto their low permeability through gastrointestinal tract membranes,suggests a better availability to the organism and, consequently, abetter bioavailability, while at the same time decreasing inter- and/orintra-patient variations.

[0094] The addition of hydrophilic agents such as, by way of nonlimitingexamples, cellulosic polymers (for example hydroxypropylmethylcelluloseor hydroxyethylcellulose or alternatively carboxymethylcellulose),polyvinylpyrrolidone derivatives (for example crospovidone) orsurfactants (for example polysorbate), capable of increasing thehydrophilicity of the preparation, is part of the invention and mayfurther improve the rate of dissolution of the complexes formed or thestability of these complexes.

[0095] These polymeric and/or surfactant hydrophilic compounds are usedduring the actual complexation of the polycarbon-chain anilidederivatives and the cyclodextrins or derivatives thereof, or else areincluded as ingredients in the excipient formula of the correspondingpharmaceutical compositions.

EXAMPLE 11

[0096] Various amounts of polysorbate 80 (Tween 80) were addedto-approximately 40 g of F12511:γ-cyclodextrin mixture (1:2 molar ratio)subjected to the kneading process. This illustrates the simultaneous useof hydrophilic compounds, in particular of polysorbates, during theactual preparation of the complexes.

[0097] These amounts appear in the table below: Mass of Percentage of γ-Mass of Mass of Tween 80 in Mass of cyclodextrin water Tween 80 themixture F12511 (g) (g) (g) (g) (%) 5.68 34.34 9.41 0 0 5.66 34.34 9.330.08 0.16 5.67 34.38 9.41 0.25 0.50 5.67 34.32 9.42 0.51 1.00 5.66 34.349.39 0.98 2.00

[0098] The second table gives the percentages of complexation of theF12511, determined by differential thermal analysis, and also theamounts of F12511 solubilized, from these complexes, in water at 37° C.after stirring for 2 hours. Percentage of Solubility of the Tween 80 inthe Percentage of F12511 in water, at mixture F12511 complexed 37° C.,after 2 h (%) (%) (μg/ml) 0 100 1.9 0.16 98 9.1 0.50 98 17.3 1.00 9725.2 2.00 100 57.8⁽¹⁾

[0099] The use of polycarbon-chain anilide derivatives, more preciselyof dodecylthiophenylacetanilide derivatives., such as(S)-2′,3′,5′-trimethyl-4′-hydroxy-α-dodecylthiophenylacetanilide orrelated derivatives thereof, the particles of which have a high specificsurface area of between 0.5 and 100 m²/g, and more particularly between5 and 50 m²/g, is also part of the invention.

[0100] The pharmaceutical compositions containing the complexes ofpolycarbon-chain anilide derivatives and of cyclodextrins, moreparticularly of dodecylthiophenylacetanilide derivatives, such as(S)-2′,3′,5′-trimethyl-41-hydroxy-α-dodecylthiophenylacetanilide(F12511) or related derivatives thereof, and of cyclodextrins, moreprecisely α-, β-, γ-cyclodextrins and derivatives thereof, such ashydroxypropyl, sulfobutyl ether or methylated derivatives, are also partof the invention.

[0101] They are more particularly intended to be administered orally orparenterally. They are then, respectively, in the form of tablets, ofgelatin capsules and of powders in sachets, of lyophilizates or ofsolutions, which are ready-to-use or are to be reconstitutedextemporaneously.

[0102] With regard to the good results concerning the increases inwater-solubility and the capacity for micellization in an aqueoussolution containing 5% of sodium lauryl sulfate, obtained for F12511 viathe F12511: cyclodextrin complexes compared to F12511 alone, it wasdecided to orally administer to dogs F12511 and theF12511:γ-cyclodextrin (1:2) complex prepared by kneading, each one beingincluded in a gelatin capsule formulation, in order to verify whether ornot the F12511 bioavailability was increased when this F12511 wascomplexed with cyclodextrins.

[0103] The characteristics of the gelatin capsules prepared are:Reference Formula with formula F2 F12511:γ- F12511 alone CD (1:2) F1251140.0 mg 40.0 mg Gamma-cyclodextrin 0 241.9 mg⁽¹⁾ excipients qs 200.0 mgqs 350.0 mg Per size 1 gelatin capsule

[0104] The gelatin capsules were administered to 6 male dogs at a rateof one gelatin capsule orally.

[0105] The mean plasma concentrations are represented in FIG. 11.

[0106] Comparisons of the areas under the curve indicate an area underthe curve for the F12511:γ-CD (1:2) complex which is 8 times greaterthan that corresponding to the reference formula with the non-complexedF12511.

[0107] Moreover, the maximum plasma concentration reached for theF12511:γ-CD (1:2) complex is almost 10 times greater than thatcorresponding to the reference formula with the non-complexed F12511.

[0108] It is clear that the bioavailability of F12511, when given orallyto dogs, is considerably increased when the F12511 is complexed with twomoles of γ-cyclodextrin.

[0109] The pharmaceutical compositions which are the subject of theinvention allow the treatment of dyslipidemias, such ashypercholesterolemia, and the prevention of atherosclerosis.

[0110] Their method of action is essentially explained by inhibition ofthe enzyme acyl cholesterol acyltransferase or ACAT.

1. A complex between ACAT-inhibiting polycarbon-chain anilidederivatives and cyclodextrins.
 2. The complex as claimed in claim 1,characterized in that the polycarbon-chain anilide derivatives aredodecylthiophenylacetanilide derivatives, such as(S)-2′,3′,5′-trimethyl-4′-hydroxy-α-dodecylthiophenylacetanilide orrelated derivatives thereof.
 3. The complex as claimed in either ofclaims 1 and 2, characterized in that the cyclodextrins are nativecyclodextrins, in particular γ-, β-, α-cyclodextrins or derivativesthereof, such as hydroxypropyl, sulfobutyl ether or methylatedderivatives.
 4. The complex as claimed in one of claims 1 to 3,characterized in that the polycarbon-chain anilide derivatives:cyclodextrin molar ratios are between 1:5 and 5:1, more particularlybetween 1:1 and 1:3, and even more particularly equal to 1:2.
 5. Amethod for preparing the complexes as claimed in one of claims 1 to 4,characterized in that the complexation of the ACAT-inhibitingpolycarbon-chain anilide derivatives and of the cyclodextrins isobtained by supplying mechanical or thermal energy or energy developedby high pressures, or by the combination of these energies.
 6. A methodfor preparing the complexes as claimed in one of claims 1 to 4,characterized in that they are obtained: a) in semi-solid medium, inparticular by kneading, according to a batch method such as preparationin a mixer, or according to a continuous method such as extrusion, or b)in solid medium, in particular by co-grinding, or c) in semi-solid orsolid medium, in particular using a gentle mechanical energy combinedwith the action of high temperatures and high pressures, or else d) inliquid medium, in particular by co-precipitation resulting from the useof suitable solvents or non-solvents.
 7. A pharmaceutical compositioncontaining the complexes as claimed in one of claims 1 to 4, moreparticularly for oral or parenteral administration thereof.
 8. Thepharmaceutical composition as claimed in claim 7, characterized in thatit also contains hydrophilic compounds used simultaneously during theactual preparation of the complexes, or added as ingredients in theexcipient formulation.
 9. The pharmaceutical composition as claimed inclaim 8, characterized in that the hydrophilic compounds are polymers,in particular cellulose or polyvinylpyrrolidone derivatives, or elsesurfactants, in particular polysorbates.
 10. The pharmaceuticalcomposition as claimed in either of claims 8 and 9, characterized inthat it contains a polycarbon-chain anilide derivative, the particles ofwhich exhibit a high specific surface area of between 0.5 and 100 m²/g,and more particularly between 5 and 50 m²/g.
 11. The use of thecomplexes as claimed in one of claims 1 to 4, for the production ofmedicines intended for the treatment of dyslipidemias, such ashypercholesterolemia, and/or for the prevention of atherosclerosis.